It is well established that many .beta.-adrenergic agents elicit more than a single biological effect following administration. Resolution of the optical isomers of these agents which contain asymmetric centers has, in many instances, demonstrated marked differences in potency between these isomers. In addition to increasing knowledge of receptor site topography, the pharmacologic profiles of the individual isomers may provide new and/or more desirable drug entities.
Previously, the optical isomers of .beta.-adrenergic agents have most generally been obtained by one of three basic methods: (1) the fractional recrystallization of chiral acid salt derivatives; (2) synthesis of the single optical isomer using chiral epoxide intermediates; and, more recently, (3) column chromatography utilizing chiral stationary phases. The difficulties associated with application of these methods are well known to practitioners in the art, specifically, the tedious and time-consuming fractional recrystallizations and repeated chromatography; requisite chiral syntheses of epoxide intermediates with the attendant complications associated with stereospecific synthesis, and size limitation of quantities obtained via chromatography. Generally, preparation of a single enantiomer by these methods is quite expensive.
Another resolving method, derivatization with a chiral organic reagent, has been used for resolution of compounds which can form derivatives. .beta.-Adrenergic agents in general have two functional moieties amenable to derivatization, i.e. secondary amino and alcohol functionalities. The resolution of amines and alcohols by derivatization with chiral acyl halides or isocyanates is well known in the chemical literature. The success of such a resolution strategy depends upon several factors, notably (1) formation of the diastereomeric derivatives in reasonably high yield, (2) facile separation of these diastereomers by chromatographic or crystallization techniques, and (3) the regeneration of the parent compound from the separated diastereomeric derivatives. To our knowledge, this technique has never been utilized for the resolution of .beta.-adrenergic propanolamines.
The following references disclose .beta.-adrenergic propanolamines having a urea moiety incorporated into their structure.
1. O'Donnell, et al, Clin. Exp. Pharmacol., 8/6, 614-615 (1981) disclose a .beta.-adrenergic agent (ICI 89963) with a urea moiety in the terminal alkyl portion of the structure. ##STR1##
2. Eckardt, et al., Die Pharmazie, 30, 633-637 (1975) disclose .beta.-blocking propanolamines with urea substituents on the aryl portion of the molecule: ##STR2## These urea compounds differ structurally from the urea intermediates of the instant process as the propanolamine nitrogen of the reference compounds is not a component of the urea grouping.
The next grouping of references relate to methods of resolution of optical isomers which are deemed most relevant to the instant process described herein.
3. J. Jacques, A. Collet, S. H. Wilen, in "Enantiomers, Racemates, and Resolutions", John Wiley & Sons, New York, N.Y. (1981), pp. 330-335. This reference describes, among other things, formation and separation of diastereomers comprising covalent derivatives of amines and alcohols. Specifically, amines may be resolved through conversion into diastereomeric ureas by reaction with optically active isocyanates; and, following separation of the diastereomeric ureas by crystallization or by chromatography, the resolved amine is recovered through pyrrolysis.
4. F. C. Whitmore in "Organic Chemistry", D. Van Nostrand Co., New York, N.Y. (1937), p. 551. This reference reports that dl-.beta.-amino-lactic aldehyde dimethyl acetal, H.sub.2 NCH.sub.2 CHOHCH(OMe).sub.2, gave diastereomeric ureas when treated with l-menthyl isocyanate, as part of a scheme to prepare optically active glyceraldehydes.
5. Kolomoietes, et al. Zh. Org. Khim., English Edition, 16/5, pp. 854-857 (1980). This reference describes kinetic resolution of secondary alcohols and amines using S-(-)-.alpha.-phenylethylisocyanate.
It is appreciated by the practitioner in the art, that derivatization of .beta.-adrenergic aryloxypropanolamines might be expected to present difficulties by virtue of the molecule containing two reactive functionalities, e.g. both an amine and an alcohol moiety.
Reference 4., supra, is the only example of which we are aware that reports diastereomeric urea derivatization by isocyanate treatment of a molecule containing both amino and hydroxy moieties. The compound being derivatized in the work mentioned by Whitmore is not related to the .beta.-adrenergic propanolamine structure. The terminal primary amino group as opposed to the secondary hydroxyl in H.sub.2 NCH.sub.2 CHOH(OMe).sub.2 would be expected to be more accessible sterically to electrophilic attack by an isocyanate. Any steric advantage of the amino group is negated in .beta.-adrenergic structures in which the amino nitrogen is further substituted with an alkyl group, which is usually branched, thereby giving a more hindered secondary amine. It would reasonably be expected prior to the instant invention that reaction of an optically active isocyanate and a .beta.-adrenergic aryloxypropanolamine would result in a complex product mixture containing both diastereomeric ureas and carbamates. In practice, it is discovered that the reaction takes place preferentially at the site of the amine moiety, even when sterically hindered, giving predominently as novel intermediates the diastereomeric urea derivatives. This reaction selectivity forms the basis for the first step of the instant process.
The other major complication accompanying derivative resolution is the regeneration of the parent compound from the separated diastereomeric derivative. It is appreciated that ureas as a class of compounds are inherently stable and generally require more stringent methods, e.g. pyrrolysis or strong hydrolyzing conditions, for their decomposition. Since many of the .beta.-adrenergic aryloxypropanolamines, especially those with sensitive substituents, would be labile under these same conditions, the regeneration step of the instant process becomes quite important.
The following references relate to methods of cleaving ureas in order to produce a parent amine.
6. Woodward, Pure Appl. Chem., 17 (1968), pp. 524-525. Woodward discloses the resolution of a racemic amine mixture by forming diastereomeric ureas with optically active .alpha.-phenylethyl isocyanate. Following separation of the diastereomers, the optically active amine is generated by pyrrolysis of the urea.
7. (a) Manske, J. American Chemical Society, 51, (1929) p. 1202. (b) Houben-Weyl "Methoden der Organische Chemie". Vierte Auflage Stickstoff-Verbindungen II, 11/1 (1957), pp. 952-953. (c) P. A. S. Smith, "The Chemistry of Open-Chain Organic Nitrogen Compounds" Volume I, W. A. Benjamin, Inc., New York, N.Y. (1965), p 270. (d) D. Barton and W. D. Ollis, in "Comprehensive Organic Chemistry" Volume II, Nitrogen Compounds, Carboxylic Acids, Phosphorus Compounds, Pergamon Press, Ltd. (1979), p. 1095. These four references are representative of the chemical literature which teaches that hydrolysis of urea compounds is not easy and usually requires prolonged heating with strong mineral acid or alkali.
A convenient mild reaction for breakdown of the useful intermediate urea derivatives, thereby regenerating the desired amine in optically active form, has been developed as part of the instant process.